1. Field of the Invention
The present invention generally relates to risk assessment, detection, diagnosis, prognosis, treatment and prevention of steroid hormone responsive cancers of mucosal epithelial tissues (i.e., glands and tissues that secrete or are bathed by secretory immunoglobulins). More particularly, the invention relates to negative (inhibitory) regulation of steroid hormone responsive cancer cell proliferation, and to the immunoglobulin inhibitors and the receptors that mediate such regulation.
2. Description of Related Art
Finding a naturally occurring biochemical defense mechanism capable of controlling neoplastic growth has been the goal of a number of researchers for many years. Use of the immune system against malignant tumors forms the basis for many anti-cancer strategies. For example, U.S. Pat. No. 5,980,896 describes certain antibodies, antibody fragments and antibody conjugates and single-chain immunotoxins directed against human carcinoma cells. Conventional anti-tumor immunotherapies rely on antibody-antigen recognition chemistry, and on targeting of antibodies against various antigenic features of tumor cells in order to trigger destruction of the tumor cells by the body's immune system or to target the tumor cells with antibody conjugates of various cytotoxic or chemotherapeutic agents. In practice, however, tumors in vivo have generally not been found to be very immunogenic and in many instances appear to be capable of evading the body's immune response. Today a great deal of anti-cancer work is directed at finding ways of increasing the immunogenicity of a tumor cell in vivo. For example, U.S. Pat. No. 6,120,763 (Fakhrai et al.) describes a method of preventing or reducing the severity of a cancer in a subject by stimulating the subject's immune response against the cancer. Many studies have attempted use of IgG as passive immunity or stimulation of natural IgG production to restrict tumor growth. As of today, there are no known vaccines for breast cancer, prostate cancer, or any other forms of mucosal cancers (Smyth M J et al. (2001) Nature Immunol 2, 293-299).
There is a second type of immune system that is very important to the function and protection of the body. The immunological function and physiological properties of the body's secretory immune system has been recognized for many years (Tomasi T B et al. (1965) J Exp Med 121, 101-124; Brandtzaeg P and Baklien K (1977) Ciba Foundation Symposium 46, 77-113; Tomasi T B (1970) Ann Rev Med 21, 281-298; Spiegelberg H L (1974) Adv Immunol 19, 259-294; Tomasi T B (1976) The Immune System of Secretions, Prentice-Hall, Englewood Clifts, N.J.; Mestecky J and McGhee J R (1987) Adv Immunol 40, 153-245). It was established that immunoglobulin A (IgA) represents 5 to 15% of the total plasma immunoglobulins in humans (Spiegelberg H L (1974) Adv Immunol 19, 259-294). IgA has a typical immunoglobulin four-chain structure (Mr 160,000) made up of two heavy chains (Mr 55,000) and two light chains (Mr 23,000) (Fallgreen-Gebauer E et al (1993) Biol Chem Hoppe-Seyler 374, 1023-1028; Kratzin H et al. (1978) Hoppe-Seylers Z Physiol Chem 359, 1717-1745; Yang C et al. (1979) Hoppe-Seylers Z Physiol Chem 360, 1919-1940; Eiffert H et al. (1984) Hoppe-Seylers Z Physiol Chem 365, 1489-1495). In humans, there are two subclasses of IgA. These are IgA1 and IgA2 that have 1 and 2 heavy chains, respectively. The IgA2 subclass has been further subdivided into A2m(1) and A2m(2) allotypes (Mestecky J and Russell M W (1986) Monogr Allergy 19, 277-301; Morel A et al. (1973) Clin Exp Immunol 13, 521-528). IgA can occur as monomers, dimers, trimers or multimers (Lüllau E et al. (1996) J Biol Chem 271, 16300-16309). In plasma, 10% of the total IgA is polymeric while the remaining 90% is monomeric. Formation of dimeric or multimeric IgA requires the participation of an elongated glycoprotein of approximately Mr 15,000 designated the “J” chain (Mestecky J et al. (1990) Am J Med 88, 411-416; Mestecky J and McGhee J R (1987) Adv Immunol 40, 153-245; Cann G M et al. (1982) Proc Natl Acad Sci USA 79, 6656-6660). Structurally, the J chain is disulfide linked to the penultimate cysteine residue of heavy chains of two IgA monomers to form a dimeric complex of approximately Mr 420,000. The general structure of the dimer has been well described in the literature (Fallgreen-Gebauer E et al (1993) Biol Chem Hoppe-Seyler 374, 1023-1028). Multimeric forms of IgA and IgM require only a single J chain to form (Mestecky J and McGhee J R (1987) Adv Immunol 40, 153-245; Chapus R M and Koshland M E (1974) Proc Natl Acad Sci USA 71, 657-661; Brewer J W et al. (1994) J Biol Chem 269, 17338-17348). The structures and chemical properties of IgA and IgM have been described in detail (Janeway C A Jr et al. (1996) Immunobiology, The Immune System in Health and Disease, Second edition, Garland Publishing, New York, pp 3-32 and pp 8-19).
Dimeric and multimeric IgA and IgM are secreted by a number of exocrine tissues. IgA is the predominant secretory immunoglobulin present in colostrum, saliva, tears, bronchial secretions, nasal mucosa, prostatic fluid, vaginal secretions, and mucous secretions from the small intestine (Mestecky J et al. (1987) Adv Immunol 40, 153-245; Goldblum R M, et al. (1996) In: Stiehm E R, ed, Immunological Disorders in Infants and Children, 4th edition, Saunders, Philadelphia, pp 159-199; Heremans J F (1970) In: Immunoglobulins, Biological Aspects and Clinical Uses, Merler E, ed, National Academy of Sciences, Wash D.C. pp 52-73; Tomasi T B Jr (1971) In: Immunology, Current Knowledge of Basic Concepts in Immunology and their Clinical Applications, Good R A and Fisher D W, eds, Sinauer Associates, Stanford, Conn., p 76; Brandtzaeg P (1971) Acta Path Microbiol Scand 79, 189-203). IgA output exceeds that of all other immunoglobulins, making it the major antibody produced by the body daily (Heremans J F (1974) In: The Antigens, Vol 2, Sela M, ed, Academic Press, New York, pp 365-522; Conley M E et al. (1987) Ann Intern Med 106, 892-899. IgA is the major immunoglobulin found in human milk/whey/colostrum (Ammann A J et al. (1966) Soc Exp Biol Med 122, 1098-1113; Peitersen B et al. (1975) Acta Paediatr Scand 64, 709-717); Woodhouse L et al. (1988) Nutr Res 8, 853-864). IgM secretion is less abundant but can increase to compensate for deficiencies in IgA secretion. J chain containing IgA is produced and secreted by plasma B immunocytes located in the lamina propria just beneath the basement membrane of exocrine cells (Brandtzaeg P (1985) Scan J Immunol 22, 111-146). The secreted IgA binds to a Mr 100,000 poly-Ig receptor positioned in the basolateral surface of most mucosal cells (Heremans J F (1970) In: Immunoglobulins, Biological Aspects and Clinical Uses, Merler E, ed, National Academy of Sciences, Wash D.C., pp 52-73; Brandtzaeg P (1985) Clin Exp Immunol 44, 221-232; Goodman J W (1987) In: Basic and Clinical Immunology, Stites D P, Stobo J D and Wells J V, eds, Appleton and Lange, Norwalk, Conn., Chapter 4). The receptor-IgA complex is next translocated to the apical surface where IgA is secreted. The binding of dimeric IgA to the poly-Ig receptor is completely dependent upon the presence of a J chain (Brandtzaeg P (1985) Scan J Immunol 22, 111-146; Brandtzaeg P and Prydz H (1984) Nature 311:71-73; Vaerman J-P et al. (1998) Eur J Immunol 28, 171-182). Monomeric IgA will not bind to the receptor. The J chain requirement for IgM binding to the poly-Ig receptor is also true for this immunoglobulin (Brandtzaeg P (1985) Scan J Immunol 22, 111-146; Brandtzaeg P (1975) Immunology 29, 559-570; Norderhaug I N et al. (1999) Crit Rev Immunol 19, 481-508). Because IgA and IgM bind to the poly-Ig receptor via their Fc domains, and because of a repeating Ig-like structure in the extracellular domains, the poly-Ig receptor classifies as a member of the Fc superfamily of immungobulin receptors (Kraj{hacek over (c)}i P et al. (1992) Eur J Immunol 22, 2309-2315; Daëron M (1997) Annu Rev Immunol 15, 203-234). During passage of IgA through the cell, its structure is modified. A Mr 80,000 fragment of the receptor containing all five of the extracellular domains becomes covalently attached to dimeric IgA to form secretory IgA (sIgA) (Fallgreen-Gebauer E et al (1993) Biol Chem Hoppe-Seyler 374, 1023-1028). The receptor that mediates the translocation has been interchangeably called the “poly-Ig receptor” (poly-Ig receptor) or the “secretory component” (Kraj{hacek over (c)}i P et al. (1992) Eur J Immunol 22, 2309-2315). Except where noted otherwise, for the purposes of the present disclosure, the term “poly-Ig receptor” refers to the full length Mr 100,000 transmembrane protein and the term “secretory component” denotes only the Mr 80,000 extracellular five domains of the receptor that become covalently attached to IgA in forming the sIgA structure (Fallgreen-Gebauer E et al (1993) Biol Chem Hoppe-Seyler 374, 1023-1028; Kraj{hacek over (c)}i P et al. (1992) Eur J Immunol 22, 2309-2315). Because of the unique structure of sIgA, it is highly resistant to acid and proteolysis (Lindh E (1975) J Immunol 114, 284-286) and therefore remains intact in secretions to perform extracellular immunological functions. IgM also binds secretory component, but not covalently (Lindh E and Bjork I (1976) Eur J Biochem 62, 271-278). However, IgM is less stabilized because of its different association with the secretory component, and therefore has a shorter functional survival time in acidic secretions (Haneberg B (1974) Scand J Immunol 3, 71-76; Haneberg B (1974) Scand J Immunol 3, 191-197). IgA and IgM are known to bind to bacterial, parasite and viral surface antigens. These complexes bind to receptors on inflammatory cells leading to destruction of the pathogen by antibody-dependent cell-mediated cytotoxicity (Hamilton R G (1997) “Human immunoglobulins” In: Handbook of Human Immunology, Leffell M S et al., eds, CRC Press, Boca Raton, Chapter 3).
The major immunoglobulins secreted as mucosal immune protectors include IgA, IgM and IgG. In human serum, the percent content of IgG, IgA and IgM are 80, 6 and 13%, respectively. In humans, the major subclasses of IgG are IgG1, IgG2, IgG3 and IgG4. These are 66, 23, 7 and 4% of the total IgG, respectively. The relative content of human immunoglobulin classes/subclasses in adult serum follow the order IgG1>IgG2>IgA1>IgM>IgG3>IgA2>IgD>IgE (Spiegelberg H L (1974) Adv Immunol 19, 259-294). When the serum concentrations of immunoglobulins are compared to those in exocrine secretion fluids, the relative contents change dramatically (Brandtzaeg P (1983) Ann NY Acad Sci 409, 353-382; Brandtzaeg P (1985) Scand J Immunol 22, 111-146). For example in colostrum (a breast fluid secretion), IgA is ≧80% of the total immunoglobulins. IgM is ≦10% of the total. IgG represents a few percent. In human colostrum and milk, IgG1 and IgG2 are the major subclasses of IgG (Kim K et al. (1992) Acta Paediatr 81, 113-118). Clearly, comparison of serum and mucosal fluid concentrations indicate selective immunoglobulin secretion. The secretion mechanism for IgA and IgM are well described. Conversely, there is a fundamental question surrounding IgG secretion. There is no “J” chain present in IgG1 and IgG2. From the known facts of transcytosis/secretion of immunoglobulins (Johansen F E et al. (2000) Scand J Immunol 52, 240-248), it is unlikely that IgG secretion is mediated by the poly-Ig receptor. An epithelial receptor specific for IgG1 has been reported in bovine mammary gland (Kemler R et al. (1975) Eur J Immunol 5, 603-608). Apparently, it preferentially transports this class of immunoglobulins from serum into colostrum. Despite this 1975 report however, the receptor has not been chemically or structurally identified nor has the mechanism of transport of IgG monomers been satisfactorily defined. Certainly no growth function was ascribed to this “IgG1 receptor” in the 1975 Kemler et al. report. It is possible that this receptor is a member of a large group now designated as Fc receptors (Fridman W H (1991) FASEB J 5, 2684-2690), but there is one study with IgG showing that of 31 different long-term human carcinoma cell lines including breast “all lines were found to be consistently Fc receptor negative” (Kerbel R S et al. (1997) Int J Cancer 20, 673-679). One possible candidate for the epithelial transport of IgG1 is the neonatal Fc receptor (Raghavan M and Bjorkman P J (1996) Annu Rev Cell Dev Biol 12, 181-220). However, there is no indication yet of the presence of this receptor in adult mucosal tissues.
All human mucus membranes are protected by the secretory immune system (Hanson L Å and Brandtzaeg P (1989) In: Immunological Disorders in Infants and Children, 3rd edition, Stiehm E R, ed, Saunders, Philadelphia, pp 169-172). The primary protector is sIgA that is produced as dimers and larger polymers. A single joining “J” chain connects IgA monomers to form the dimers and polymers (Garcia-Pardo A et al. (1981) J Biol Chem 256, 11734-11738), and connects monomers of IgM to give pentamers (Niles M J et al. (1995) Proc Natl Acad Sci USA 92, 2884-2888). This critical joining endows these structures with a very important immunological property. Dimeric and polymeric sIgA have a high antigen binding valence that effectively agglutinates/neutralizes bacteria and virus (Janeway C A Jr et al. (1999) Immunobiology, The Immune System in Health and Disease, 4th edition, Garland Publishing, New York, pp 326-327). Also, sIgA shows little or no complement activation. This means that it does not cause inflammatory responses (Johansen F E et al. (2000) Scand J Immunol 52, 240-248). In addition, the fact that IgA exists as two separate forms is significant (Loomes L M et al (1991) J Immunol Methods 141, 209-218). The IgA1 predominates in the general circulation. In contrast, IgA2 is often higher in mucosal secretions such as those from breast, gut, and respiratory epithelium, salivary and tear glands, the male and female reproductive tracts, and the urinary tracts of both males and females. This difference in proportions is important to immune protection of mucosal surfaces. Although the secretory form of IgA1 is by and large resistant to proteolysis (Lindh E (1975) J Immunol 114, 284-286), a number of different bacteria secrete proteolytic enzymes that cleave it into Fab and Fc fragments (Wann J H et al. (1996) Infect Immun 64, 3967-3974; Poulsen K et al. (1989) Infect Immun 57, 3097-3105; Gilbert J V et al. (1988) Infect Immun 56, 1961-1966; Reinholdt J et al (1993) Infect Immun 61, 3998-4000; Blake M S and Eastby C (1991) J Immunol Methods 144, 215-221; Burton J et al. (1988) J Med Chem 31, 1647-1651; Mortensen S B and Kilian M (1984) Infect Immun 45, 550-557; Simpson D A et al. (1988) J Bacteriol 170, 1866-1873; Blake M S and Swanson J et al. (1978) Infect Immun 22, 350-358; Labib R S et al. (1978) Biochim Biophys Acta 526, 547-559). In effect, the bacterial proteinases negate the neutralizing effects of multivalent sIgA1. In contrast, because of structural differences (Chintalacharuvu K R and Morrison S L (1996) J Immunol 157, 3443-3449), IgA2 lacks sites required for proteolysis. This makes IgA2 more resistant to bacterial digest than IgA1 (Hamilton R G (1997) “Human immunoglobulins” In: Handbook of Human Immunology, Leffell M S et al., eds, CRC Press, Boca Raton, Chapter 3). With regard to IgM, its function is somewhat different. IgM antibodies serve primarily as efficient agglutinating and cytolytic agents. They appear early in the response to infection and are largely confined to the bloodstream. Whether secreted or plasma-borne, IgM is a highly effective activator of the classical complement cascade. It is less effective as a neutralizing agent or an effector of opsinization (i.e. facilitation of phagocytosis of microorganisms). Nonetheless, IgM complement activation causes lysis of some bacteria. The effects of the IgG class are more encompassing. All four subclasses cause neutralization, opsinization and complement activation to defend against mucosal microorganisms. IgG1 is an active subclass in this regard (Janeway C A Jr et al. (1999) Immunobiology, The Immune System in Health and Disease, 4th edition, Garland Publishing, New York pp 326-327).
With regard to breast cancer and prostate cancer etiology, there has been only limited attention given to the role of the immune system. Other issues have been considered more important for placing individuals in the at-risk groups for developing cancer in general and breast cancer specifically. This has led to searches for risk factors. Advances certainly have been made. We now have the benefit of the investment of scientific effort and volume of new information that was obtained. Breast cancer is one useful example of our advances. There have been several reviews of this topic published since 1979 (Kelsey J L (1979) Epidemiol Rev 1, 74-109; Kelsey J L and Berkowitz G S (1988) Cancer Res 48, 5615-5623; Kelsey J L and Gammon M D (1990) Epidemiol Rev 12, 228-240; Colditz G A (1993) Cancer 71, 1480-1489; Alberg A J and Helzlsouer K J (1997) Current Opinion Oncology 9, 505-5111). Although reproductive factors, body build, oral contraceptives, estrogen replacement therapy, diethylstilbestrol, hormonal imbalances, diet (particularly high fat consumption), alcohol consumption, radiation, familial aggregation and heredity have been studied, and some of these identified as risk factors, there remains no known cause of the 70% or more of breast cancers now known as “sporadic” because they appear to occur randomly in the population and certainly without any known genetic pattern. Plainly stated, for the vast majority of women who develop breast cancer, there is no known genetic cause. Even with the best applications of the epidemiology cited above, the answer has not been forthcoming for this majority.
The only cases where there is a defined genetic origin of breast cancer involve the BRCA1 and BRCA2 genes. The BRCA1 gene has been cloned, sequenced and localized to chromosome 17 (Hall J M et al. (1990) Science (Wash D.C.) 250, 1684-1689; Bowcock A M (1993) Breast Cancer Res Treat 28, 121-135; Miki Y et al. (1994) Science (Wash D.C.) 266, 66-71). Another gene, BRCA2, has also been identified and linked to chromosome 13q (Wooster R et al. (1995) Nature (Lond) 378, 789-792; Tavigian S V et al. (1996) Nature Genet 12, 333-337). BRCA1 gene lesions are linked to breast and ovarian cancer. BRCA2 is more associated with ovarian cancer than breast cancer. Together, these two genes are thought to account for most of the inheritable/familial breast cancer in the United States (Krainer M et al. (1997) New Eng J Med 336, 1416-1421). However, one important fact that must be recognized is that these genes are probably carried by fewer than 400 women in the United States and therefore are responsible for a relatively small number of human breast cancers (King M-C et al (1993) JAMA 269, 1975-1980; Biesecker B B et al. (1993) JAMA 269, 1970-1974). Although these genes continue to be studied intensively, it is far from clear that they have a significant causative role in the 70% or more of “sporadic” non-inherited breast cancers. In fact, the essential point is that the origin of the vast majority of breast cancers remains unknown.
Currently these two genes, BRCA1 (Lynch H et al. (1978) Cancer 41, 1543-1549; Hall J M et al. (1990) Science (Wash D.C.) 250, 1684-1689; Narod S A et al. (1991) Lancet 338, 82-83; Steichen-Gersdorf E et al. (1994) Am J Hum Genet 55, 870-875; Miki Y et al. (1994) Science (Wash D.C.) 266, 66-71; Smith S et al. (1992) Nature Genet 2, 128-131) and BRCA2 (Wooster R et al. (1994) Science (Wash D.C.) 265, 2088-2090; Wooster R et al. (1995) Nature 378, 789-792), have been related to early onset of familial (autosomal dominant) breast and ovarian cancer. In contrast to BRCA1, which is linked predominantly to female cancers, BRCA2 is also linked to male breast cancer. As pointed out above, about 1% of the breast cancers occurring in the United States are related to those genes (Easton F D et al. (1994) Lancet 344, 761). Their gene sequences have been fully characterized and in the case of BRCA1, many mutations have been identified (Shattuck-Eidens D et al. (1995) JAMA 273, 535-552; Simard J et al. (1994) Nature Genet 8, 392-398; Castilla L H et al. (1994) Nature Genet 8, 387-391). Mutations in these genes were initially considered to confer more than 80% lifetime risk for developing breast and/or ovarian cancer (Easton D F et al. (1993) Am J Hum Genet 52, 678-701). More recent results have reduced the roles of BRCA1 and BRCA2 in breast cancers (Struewing J P et al. (1997) New Eng J Med 336, 1401-1408; Couch F J et al. (1997) New Eng J Med 336, 1409-1415; Krainer M et al. (1997) New Eng J Med 336, 1416-1421). BRCA1 and BRCA2 may have roles in sporadic breast and ovarian cancers, but to what extent is open to question (Futreal P A et al. (1994) Science (Wash D.C.) 266, 120-122; Merajver S D et al. (1995) Nature Genet 9, 439-443). In addition to BRCA1 and BRCA2, the tumor suppressor gene p53 has been implicated in both familial (germ line) and sporadic breast cancers (Malkin D et al. (1990) Science (Wash D.C.) 250, 1233-1238; Coles C et al. (1992) Cancer Res 52, 5291-5298; Elledge R M and Allred D C (1994) Breast Cancer Res Treat 32, 39-47). However, this genetic link accounts for at most 25% of breast cancers. It is possible that germ line mutations in p53 also are related to a fraction of prostate cancers (Malkin D et al. (1990) Science (Wash D.C.) 250, 1233-1238). One area of active investigation focuses on the 70% of breast cancers termed “sporadic,” because they are not familial and not related to any currently known epidemiological risk factor. An effective means of assessing genetic risk for sporadic breast cancers, prostate cancers, and other cancers of glandular/mucosal epithelial tissues, simply does not exist today in the conventional medical arsenal against cancer.
The genetic origin of prostate cancers has been even more elusive than that of breast cancers. Although a gene for prostate cancer susceptibility has been localized to chromosome 17q, it does not appear to be related to BRCA1 (PCT Pub. App. No. WO0027864). Other prostate cancer susceptibility genes have been localized to chromosomes 13q (Cooney K A et al. (1996) Cancer Res 56, 1142-1145) and to chromosomes 8p, 10q and 16q (Veronese M L et al. (1996) Cancer Res 56, 728-732). From the data available, it is clear that the genetic origin of prostate cancer has not been identified. This fact alone opens the issue of cause. While genetic analysis will continue to be important, it will not provide the essential information about what is causing breast and prostate cancer.
In a conceptually different approach to identifying cancer-related genes, Dr. Ruth Sager has suggested a departure from the conventional avenues of identifying cancer-related genes by searching for mutations (Class I genes), and instead or additionally focusing on the role of expression genetics in cancer (Class II genes) (Sager R (1997) Proc Natl Acad Sci 94, 952-955). Dr. Sager has proposed that far more genes are down regulated at the transcriptional level in cancer cells than are mutated and that crucial “oncogenic” molecules may not be mutated. Consistent with that proposition others have reported (Thompson M F et al. (1995) Nature Genet 9, 444-450) that reduced amounts of BRCA1 mRNA, representing down-regulation of the wild-type gene, were found in primary tumors of the nonfamilial disease. Characterization of other genes whose expression is altered in cancer cells, and understanding their functions, will provide penetrating insight into the regulatory interactions that have been upset in cancer.
With regard to the origins of mucosal cancer, and especially breast and prostate, there has been little advance. In general, it is thought that environmental carcinogens are the origin. However, this has yet to be proven. Another familiar concept is the idea that bacteria may be involved in carcinogenesis (oncogenesis). For example, see Parsonnet J (1995) Environ Health Perspect 103 (Suppl), 263-268; Mackowiak P A (1987) Am J Med 82, 79-97; Cassell G H (1998) Emerg Infect Dis 4, 475-487; Nauts H C (1989) Cancer Surv 8, 713-723; Venitt S (1996) Environ Health Perspect 104 (Suppl), 633-637; Miller J H (1996) Cancer Surv 28, 141-153; Buiuc D and Dorneanu O (1989) Rev Med Chir Soc Med Nat Iasi 93, 223-227).
Involvement of bacteria, or other infectious agents, in some types of lymphoid cancers such as Hodgkin's disease and leukemia has been suggested (Comment of Editor: Infective cause of childhood leukaemia (1989) Lancet 1 (1829), 94-95; Serraino D et al. (1991) Int J Cancer 47, 352-357; Glaser S L and Jarrett R F Baillieres (1996) Clin Haematol 9401-416; Wolf J and Diehl V (1994) Ann Oncol 5 (Suppl 1), 105-111).
Studies suggesting that Helicobacter pylori is directly causative in gastric cancer have recently been described. H. pylori is the only bacterium known to date to have been classified as a Class I carcinogen by the International Agency for Research on Cancer (IARC). This classification indicates that by generally accepted scientific standards (Nyren O (1998) Semin Cancer Biol 8, 275-283) this microorganism is now generally considered to be a causative factor in development of gastric cancers in infected humans. Recently it has been reported that Chlamydia trachomatis infection is strongly associated with subsequent development of invasive cervical squamous cell carcinoma (Anttila T et al. (2001) JAMA 283, 47-51). The possibility that bacteria are involved in large bowel/colon cancer has also been mentioned (McBurney M I et al. (1987) Nutr Cancer 10, 23-28), however no firm conclusions have been reached as yet.
Finally, the issue of prevention deserves special comment. There are no known methods of preventing cancer other than observing life style changes and environmental changes that place individuals in the low risk groups. Tamoxifen has been considered as a potential “prevention” for breast cancer in high risk women, but as yet has not been widely accepted because of the physiologic and endocrine aberrations caused by this agent when used long term. In short, even though prevention is remarkably pressing, there has been a dearth of studies of new methods that do not disrupt the normal lifestyles and reproductive capacity of women.
Conventional immunological approaches to treating malignant tumors have generally proven inadequate. In addition, except for recent advances with respect to Helicobacter pylori and Chlamydia trachomatis (Anttila T et al. (2001) JAMA 283:47-51), anti-bacterial approaches for combating the cause(s) of malignant transformation do not appear promising. Relying only on the existing technologies, effective diagnostic and therapeutic agents, treatments and preventatives for widespread use in breast and prostate cancers, and cancers of other glandular/mucosal epithelial tissues, do not appear to be on the near horizon.